EP0463969A1 - Neue 4-Aminobuttersäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneizubereitungen - Google Patents

Neue 4-Aminobuttersäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneizubereitungen Download PDF

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Publication number
EP0463969A1
EP0463969A1 EP91401739A EP91401739A EP0463969A1 EP 0463969 A1 EP0463969 A1 EP 0463969A1 EP 91401739 A EP91401739 A EP 91401739A EP 91401739 A EP91401739 A EP 91401739A EP 0463969 A1 EP0463969 A1 EP 0463969A1
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Prior art keywords
formula
radical
base
compounds
pharmaceutically acceptable
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EP91401739A
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English (en)
French (fr)
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EP0463969B1 (de
Inventor
Michel Debaert
Pascal Berthelot
Claude Vaccher
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ADIR SARL
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ADIR SARL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel compounds of 4-amino butyric acid, their preparation process and the pharmaceutical preparations containing them.
  • arylpropionic compounds are known in the literature, which in particular have analgesic and anti-inflammatory properties.
  • Baclofen or 4-amino 3- (4-chlorophenyl) butyric acid, agonist compound of GABA B receptors used in human therapy for its antispastic properties.
  • Other 4-amino 3-aryl butyric acids, in particular heteroaryl butyric compounds have also been described (J. Med. Chem. 1987, 30 , 743 - 746), showing an affinity for the GABA B receptor.
  • the compounds of the present invention have, compared to the compounds of the prior art, a very selective and clearly greater affinity. In addition, some of them antagonize the excitation induced by convulsants at doses lower than that of Baclofen. Others have the property of stimulating the synthesis of cyclic AMP in the cerebral cortex, thus increasing the metabolic capacities of the brain. The intensity of this affinity for the GABA B receptor and the power of their activity allow, in human or animal therapy, the administration of lower doses of the compounds of the invention. This reduced dosage goes hand in hand with a reduction in the side effects which can be observed with less active compounds since it is generally accepted that the toxicity is not linked to the pharmacological mechanism of action, but that it essentially depends of the chemical structure of the compounds.
  • small amounts of the compounds of the invention produce an effect comparable to that obtained with much larger amounts of compounds of the prior art; the risks of toxic manifestations, in particular liver, are greatly reduced.
  • This advantage is particularly interesting for the fragile populations to which the compounds are addressed, generally subjects suffering from spastic disorders or elderly subjects (disease of Alzheimer's, senile lunatics or those suffering from senescent disorders), populations in which the liver functions are often already disturbed.
  • the invention relates to new compounds of 4-amino butyric acid corresponding to the general formula (I): in which :
  • R1 represents a hydroxy, amino, lower alkylamino or lower alkoxy group, or a halogen atom
  • R2 represents a hydrogen atom, a lower alkyl radical, a lower acyl radical, or a lower alkoxycarbonyl radical
  • X represents an oxygen or sulfur atom or an NH group
  • Y represents a carbon, oxygen or nitrogen atom
  • R′1 and R′2 identical or different represent a halogen or hydrogen atom or a lower alkyl or lower alkoxy, hydroxy, nitro radical, amino, lower alkylamino or trifluoromethyl, with the proviso that when X is an oxygen atom, Y is a carbon atom and R′1 and R2 each is a hydrogen atom, then R′ Treatment cannot represent either a hydrogen atom or a methoxy group
  • Z represents an oxygen or sulfur atom or an NH group
  • T represents a carbon or nitrogen atom
  • R′3 and R′4 identical or different represent a radical chosen from hydrogen, halogen, lower alkyl or alkoxy, hydroxy, nitro, amino, lower alkylamino or trifluoromethyl, with the proviso that when Z is a sulfur atom, T is a carbon atom and R′3 is a hydrogen atom, R′4 cannot be a methyl group or a hydrogen, chlorine, or bromine atom, and that when Z is an oxygen atom, T is a carbon atom and R′3 is a hydrogen atom, R′4 cannot be a hydrogen atom or a methyl group,
  • an aromatic radical with 6 vertices including in its carbon skeleton of 1 to 3 nitrogen atoms and attached to a benzene ring, each of these 2 rings possibly being substituted,
  • the invention also extends to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: in which R has the same meaning as in formula (I), that we can :
  • R1 ⁇ - H in which R1 ⁇ represents an amino, lower alkylamino or lower alkoxy group, to lead to a compound of formula (I) for which R1 represents an amino, lower alkylamino or lower alkoxy group,
  • the compounds of formula (I) have interesting pharmacological properties. They have a very important and selective affinity for the GABA B receptor, greater than that of the derivatives of the prior art.
  • GABA B receptor antagonist activity Some of them have GABA B receptor antagonist activity and as such can be administered in the treatment of memory disorders, mental disorders of senescence, as well as in the treatment of Alzheimer's disease.
  • a subject of the present invention is also pharmaceutical compositions containing the derivatives of formula (I), or one of their addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert excipients or vehicles, non-toxic, pharmaceutically acceptable.
  • compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal, rectal, perlingual, ocular or pulmonary administration and in particular injectable preparations, aerosols, eye or nasal drops, simple or coated tablets, sublingual tablets, capsules, packages, suppositories, creams, ointments, dermal gels ...
  • the dosage varies according to the patient's age and weight, the route of administration, the nature of the condition and the treatments. possibly associated and ranges between 1 mg and 1 gram per 24 hours.
  • the starting raw materials are described in the literature or can be prepared in a similar manner.
  • the infrared spectra were carried out in the form of a potassium bromide tablet containing approximately 1% of the product to be analyzed.
  • Acute toxicity was assessed after oral administration in groups of 5 mice (20 ⁇ 2 grams) in increasing doses (0.05; 0.1; 0.25; 0.50; 0.75 g / kg). The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment.
  • the compounds of the invention antagonize the excitatory activity induced by convulsive agents in hippocampal preparations.
  • the inhibition is expressed as a percentage of excitation relative to the initial rate, which makes it possible to complete an inhibitory concentration 50 (IC50).
  • IC50 inhibitory concentration 50
  • the compounds of the invention have an IC50 of between 5 and 20 ⁇ M, baclofen in this test has an IC50 close to 50 ⁇ M.
  • test compounds are administered at a dose of 10 mg / kg intraperitoneally in the OF1 / IFFA Credo strain mouse. 24 hours after the last injection, the animals are sacrificed by freezing, the cAMP present in these cerebral structures is assayed by radioimmunology according to the Amersham method (specific binding protein). Certain compounds of the invention appear to be capable of greatly increasing the cerebral synthesis of cyclic AMP.
EP91401739A 1990-06-27 1991-06-27 Neue 4-Aminobuttersäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneizubereitungen Expired - Lifetime EP0463969B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9008093 1990-06-27
FR9008093A FR2663934B1 (fr) 1990-06-27 1990-06-27 Nouveaux derives de l'acide 4 - amino butyrique, leur procede de preparation et les preparations pharmaceutiques qui les contiennent.

Publications (2)

Publication Number Publication Date
EP0463969A1 true EP0463969A1 (de) 1992-01-02
EP0463969B1 EP0463969B1 (de) 1995-02-08

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EP91401739A Expired - Lifetime EP0463969B1 (de) 1990-06-27 1991-06-27 Neue 4-Aminobuttersäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneizubereitungen

Country Status (15)

Country Link
US (2) US5162364A (de)
EP (1) EP0463969B1 (de)
JP (1) JPH04243853A (de)
AT (1) ATE118213T1 (de)
AU (1) AU637242B2 (de)
CA (1) CA2045445A1 (de)
DE (1) DE69107250T2 (de)
DK (1) DK0463969T3 (de)
ES (1) ES2071250T3 (de)
FR (1) FR2663934B1 (de)
GR (1) GR3015796T3 (de)
IE (1) IE65593B1 (de)
OA (1) OA09373A (de)
PT (1) PT98100A (de)
ZA (1) ZA914969B (de)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004532A1 (en) * 1992-08-19 1994-03-03 Mcneilab, Inc. 3-oxo-pyrido(1,2-a^_)benzimidazole-4-carboxyl and 4-oxo-azepino(1,2-a^_)benzimidazole-5-carboxyl derivatives useful in treating central nervous system disorders
FR2722192A1 (fr) * 1994-07-06 1996-01-12 Adir Nouveaux derives de l'acide 4-amino butyrique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2000057862A2 (en) * 1999-03-25 2000-10-05 Novartis Ag Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases
US6576626B2 (en) 1999-12-09 2003-06-10 Astrazeneca Ab Aminopropylphosphinic acids
US6596711B1 (en) 1999-12-09 2003-07-22 Astrazeneca Ab (Aminopropyl)methylphosphinic acids
US7319095B2 (en) 1999-12-09 2008-01-15 Astrazeneca Ab Use of GABAB receptor agonists
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2258357A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese mit Acetylcholinesterasehemmer
EP2275095A2 (de) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese durch modulation des Muscarinrezeptors
EP2314289A1 (de) 2005-10-31 2011-04-27 Braincells, Inc. Gaba-rezeptor-vermittelte modulation von neurogenese
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
EP2343073A2 (de) 2003-12-11 2011-07-13 Sepracor Inc. Kombination eines Beruhigungsmittels und eines Neurotransmittermodulators und Verfahren zur Verbesserung der Schlafqualität und Behandlung von Depressionen
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
WO2011113904A1 (en) 2010-03-17 2011-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Medicaments for the prevention and treatment of a disease associated with retinal ganglion cell degeneration
EP2377531A2 (de) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation
EP2377530A2 (de) 2005-10-21 2011-10-19 Braincells, Inc. Modulation von Neurogenese durch PDE-Hemmung
EP3753410A2 (de) 2010-09-28 2020-12-23 The Regents Of The University Of California Kombinationen enthaltend gaba agonisten zur behandlung von hyperglyzemie

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AR033779A1 (es) * 2001-06-08 2004-01-07 Astrazeneca Ab Compuestos utiles en la enfermedad de reflujo
US7109239B2 (en) 2003-08-20 2006-09-19 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
EP2354120A1 (de) 2003-08-20 2011-08-10 XenoPort, Inc. Synthese von Acyloxyalkylcarbamat-Prodrugs und Zwischenprodukten davon
SE0401653D0 (sv) * 2004-06-24 2004-06-24 Astrazeneca Ab New compounds
US7812026B2 (en) 2005-12-23 2010-10-12 Astrazeneca Ab Imidazole derivatives having a positive allosteric GABAB receptor modulator effect and methods of use
KR20080091452A (ko) * 2005-12-23 2008-10-13 아스트라제네카 아베 위장 장애의 치료를 위한 이미다졸 유도체
KR20080080214A (ko) * 2005-12-23 2008-09-02 아스트라제네카 아베 헤테로시클릭 ｇａｂａ-ｂ 조절제
JP2009521427A (ja) * 2005-12-23 2009-06-04 アストラゼネカ・アクチエボラーグ 胃食道逆流症及び過敏性腸症候群の治療のためのピラゾール
EP1968946A4 (de) * 2005-12-23 2010-05-05 Astrazeneca Ab Imidazole als modulatoren des gaba-b-rezeptors
CA2651862A1 (en) 2006-05-09 2007-11-22 Braincells, Inc. 5 ht receptor mediated neurogenesis
US20080262064A1 (en) * 2007-04-18 2008-10-23 Astrazeneca Ab Novel Compounds For The Treatment Of GI Disorders 682
KR20100015648A (ko) * 2007-04-18 2010-02-12 아스트라제네카 아베 양성 알로스테릭 ｇａｂａｂ 수용체 조절제 효과를 갖는 크산틴 화합물

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004532A1 (en) * 1992-08-19 1994-03-03 Mcneilab, Inc. 3-oxo-pyrido(1,2-a^_)benzimidazole-4-carboxyl and 4-oxo-azepino(1,2-a^_)benzimidazole-5-carboxyl derivatives useful in treating central nervous system disorders
FR2722192A1 (fr) * 1994-07-06 1996-01-12 Adir Nouveaux derives de l'acide 4-amino butyrique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2000057862A2 (en) * 1999-03-25 2000-10-05 Novartis Ag Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases
WO2000057862A3 (en) * 1999-03-25 2001-08-09 Novartis Ag Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases
US6576626B2 (en) 1999-12-09 2003-06-10 Astrazeneca Ab Aminopropylphosphinic acids
US6596711B1 (en) 1999-12-09 2003-07-22 Astrazeneca Ab (Aminopropyl)methylphosphinic acids
US6841698B2 (en) 1999-12-09 2005-01-11 Astrazeneca Ab Aminopropylphosphinic acids
US7319095B2 (en) 1999-12-09 2008-01-15 Astrazeneca Ab Use of GABAB receptor agonists
US7807658B2 (en) 1999-12-09 2010-10-05 Astrazeneca Ab Use of GabaB receptor agonists
EP2343073A2 (de) 2003-12-11 2011-07-13 Sepracor Inc. Kombination eines Beruhigungsmittels und eines Neurotransmittermodulators und Verfahren zur Verbesserung der Schlafqualität und Behandlung von Depressionen
EP2258358A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese mit Acetylcholinesterasehemmer
EP2258359A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese durch Modulation des Muscarinrezeptors mit Sabcomelin
EP2258357A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese mit Acetylcholinesterasehemmer
EP2275095A2 (de) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese durch modulation des Muscarinrezeptors
EP2275096A2 (de) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese durch modulation des Muscarinrezeptors
EP2377530A2 (de) 2005-10-21 2011-10-19 Braincells, Inc. Modulation von Neurogenese durch PDE-Hemmung
EP2314289A1 (de) 2005-10-31 2011-04-27 Braincells, Inc. Gaba-rezeptor-vermittelte modulation von neurogenese
EP2377531A2 (de) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation
EP2382975A2 (de) 2006-05-09 2011-11-02 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
WO2011113904A1 (en) 2010-03-17 2011-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Medicaments for the prevention and treatment of a disease associated with retinal ganglion cell degeneration
EP3753410A2 (de) 2010-09-28 2020-12-23 The Regents Of The University Of California Kombinationen enthaltend gaba agonisten zur behandlung von hyperglyzemie

Also Published As

Publication number Publication date
ATE118213T1 (de) 1995-02-15
US5278166A (en) 1994-01-11
CA2045445A1 (fr) 1991-12-28
FR2663934B1 (fr) 1994-06-03
IE65593B1 (en) 1995-11-01
FR2663934A1 (fr) 1992-01-03
AU7929491A (en) 1992-01-02
DK0463969T3 (da) 1995-07-10
JPH04243853A (ja) 1992-08-31
US5162364A (en) 1992-11-10
GR3015796T3 (en) 1995-07-31
OA09373A (fr) 1992-09-15
EP0463969B1 (de) 1995-02-08
DE69107250D1 (de) 1995-03-23
ZA914969B (en) 1992-04-29
IE912224A1 (en) 1992-01-01
PT98100A (pt) 1992-03-31
ES2071250T3 (es) 1995-06-16
AU637242B2 (en) 1993-05-20
DE69107250T2 (de) 1995-09-21

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